Despite the effectiveness of combined antiretroviral therapy (CART) to suppress HIV replication, HIV- associated Neurocognitive Disorders (HAND) continues to be major causes of morbidity and mortality. The management of HAND in this growing population will require new therapeutics to protect the CNS. Prominent neuroimmune activation is evident during the first months following HIV transmission, and brain inflammation persists in many patients despite CART. Sustained neuroinflammation in HIV-infected subjects is thought to contribute to neurological damage, in part by promoting the transmigration of leukocytes from the periphery into the CNS. It is not currently understood how CNS inflammation is communicated to the peripheral immune system. Our data suggests that brain neutral sphingomyelinase-2 (nSMase2) is a key regulator of this neuroimmune axis. nSMase2 activity is up-regulated by inflammatory cytokines, HIV-proteins and calcium to induce the release of exosomes from stimulated astrocytes. Exosomes are lipoprotein complexes that appear to carry inflammatory signals to periphery, and modulate the activation of leukocytes. The findings from this project will lead to a better molecular understanding of neuroimmunity that will aid on the development of a new class of neuroprotective drugs that reduce neuroinflammation by inhibition of nSMase2. PUBLIC HEALTH RELEVANCE: Although combined antiretroviral therapies are able to suppress HIV replication, the cumulative prevalence of HIV-Associated Neurocognitive Disorders (HAND) has not decreased, and may be increasing. New therapies are required to protect the CNS in HIV-infected individuals. In this application we propose to better understand the molecular mechanisms by which HIV-1 proteins, and soluble mediators released from HIV- infected macrophages regulate neuroinflammation and further elucidate interactions of the CNS with the immune system that evoke the transmigration of leukocytes into brain parenchyma.